Typically, surgery, radiotherapy and chemotherapy are used alone or in combination in the treatment of cancer. Of these cancer therapies, radiotherapy is widely used over a yearly increasing number of cancer patients.
Radiotherapy is now essential for the treatment of various cancers, but the radiation resistance of cancer cells and the damage to normal tissues caused by high doses of radiation are the main causes of a lowered efficiency of radiotherapy. Studies have been conducted into drugs that enhance radiation sensitivity (hereinafter referred to as “radiation sensitivity enhancers”) in order to increase the efficiency of radiotherapy. Most of the radiation sensitivity enhancers developed thus far are for anticancer agents, such as Taxol, cisplatin, etc.
Also, tirapazamine was known as a radiation sensitivity enhancer which has no anticancer activity, but is known to act on hypoxic tumor cells only. Further, it is not effectively delivered into the inside of tumor tissue due to the characteristic internal pressure of hypoxic tumors, resulting in a low effect on radiotherapy.
However, in combination with radiotherapy, the anticancer agents which enhance radiation sensitivity are limitedly used because they cause side effects, that is, inflammation around radiation-treated areas, gastroenteric trouble, nausea, vomiting, diarrhea, etc.
In particular, central nervous system cancer occurs from different cell lineages including glia, such as astrocytes and ologodendrocytes. Astrocytomas (astrocytic tumors) may be divided into a diffuse type and a localized type depending on interaction with adjacent microenvironments. Localized astrocytoma grows with a limitedly invasive potential and a marked border to the surrounding regions whereas diffuse astrocytoma shows a peritumoral margin and invasion into cells distal to the primary lesion irrespective of tumor grade. Per the WHO (World Health Organization) classification, diffuse astrocytoma may be classified as low-grade diffuse astrocytoma (Grade II), anaplastic astrocytoma (Grade III) and glioblastoma multiforme (Grade IV; GBM) in the order of increasing malignancy. All three grades of these diffuse astrocytomas are invasive. Particularly, GBM is more malignant than the other astrocytomas in terms of proliferation, necrosis and hypoxia, angiogenesis, invasion to the support structure of the brain, and recurrence rate, and metastasis. Therefore, various attempts have been made to enhance the efficiency of treatment of these cancers. However, chemotherapy alone is insufficient for treatment of astrocytoma. Radiotherapy is also problematic in that the cancer cells become resistant to radiation.
In addition, along with surgery and treatment with anticancer agents, as mentioned above, radiotherapy is one of the most widely used regimens for brain tumors. However, despite surgery, chemotherapy, radiotherapy or a combination of therapies (e.g. radiotherapy and chemotherapy, or surgery and radiotherapy), WHO-Grade IV GBM shows poor prognosis (recurrence), with a median survival time less than about one year and a five-year survival rate less than 5%. Of the therapies for brain tumor, radiotherapy works by damaging the DNA of cells, thus inhibiting the cell cycle (DNA damage checkpoint) or inducing apoptosis to remove abnormal cells. However, problems with radiotherapy are the inherent resistance of cancer cells to radiation and the increase of radiation-resistance, which may lead to recurrence of the cancer. Further, radiation-resistant cancer cells become resistant to anticancer agents.
Therefore, there is an imperative need for radiation sensitivity enhancers that make cancer cells of inherent radiation resistance sensitive to radiation and optimize radiotherapy with the fewest number of side effects.
MicroRNAs, which are small regulatory RNA molecules found in various cancers, are now suggested as new targets for the treatment of cancer. MicroRNAs negatively regulate their target mRNAs by degradation or translational repression, thus functioning as tumor suppressors or oncogenes. Recent studies have reported the microRNA let-7 as an important tool for enhancing cytotoxic anticancer treatment by virtue of the ability thereof to alter radiation response. Under this background, the present inventors have studied the development of radiation sensitivity enhancers with an emphasis on microRNAs playing an important role in the post-transcriptional regulation mechanism.
It is reported that microRNA-21 shows high expression levels in the GBM samples of almost all patients and is overexpressed in various cancers. This report suggests that microRNA-21 serves as an oncogene of various cancers. In addition, microRNA-21 is reported to be involved in the regulation of apoptosis, cell proliferation and cell migration in breast cancer cell lines, colorectal cancer cell lines and other cancer cell lines. However, neither relationship between microRNA-21 overexpression and radiation resistance nor the enhancement of radiation sensitivity by microRNA-21 have thus far been reported in prior art.
Leading to the present invention, intensive and thorough research into radiation sensitivity enhancers, conducted by the present inventors, resulted in the finding that the expression level of microRNA-21 is closed related with radiation resistance and that a microRNA-21 inhibitor effectively enhances the sensitivity of cancer cells to radiation.